Plant‐Derived

Research has examined the effects of cannabis or cannabinoids on chronic pain, particularly neuropathic pain, and has found low‐ to moderate‐quality evidence that these medicines produced better pain relief than placebos [13, 14]. Resiniferatoxin (RTX), produced by euphorbias, is effective as a long‐duration, nonopioid single‐administration treatment for bone cancer pain [15]. In recent laboratory studies, conolidine, derived from Tabernaemontana divaricata, is efficacious in pain assays and appears to have analgesic properties; however, its mechanism of action remains unknown [16]. There is some evidence that enteric‐coated peppermint oil capsules may be modestly efficacious in reducing abdominal pain associated with irritable bowel syndrome (IBS) [17]. Devil’s claw and white willow bark (taken orally) may be helpful for low‐back pain over the short term [18]. Two compounds in kratom (Mitragyna speciosa) leaves, mitragynine and 7‐hydroxymitragynine, interact with opioid receptors in the brain, decreasing pain when taken in high doses [19]; however, to date, there are no clinical trials to evaluate the health effects of kratom or to determine if kratom is an effective or safe treatment for any pain condition or for opioid addiction.

Challenges in the assessment of plant products include their complexity and variability, including possible instability of active components or the presence of impurities, conflicting or unreliable conclusions in the literature, and low statistical power of studies [20]. Further, there is a paucity of data on the safety of many products, including the safety of their use in a 21st century context (e.g. if taken with modern prescription drugs) [20, 21, 22] and their appropriate use in the context of traditional or indigenous practices.

Microbial‐Derived

Botulinum toxin may relieve pain by blocking substance P and calcitonin gene‐related peptide (CGRP) within the central nervous system, leading to reduction of central sensitization. It may also cause peripheral decreases of substance P, CGRP, glutamate, and TRPV receptor translocation, leading to a block of peripheral sensitization [23]. In addition, anthrax toxins are being studied as a molecular platform to target pain, and asymptomatic bacteriuria (ASB) strains of E. coli are being investigated for their analgesic properties [24]. There is some evidence that suggests some probiotics may improve abdominal pain from IBS; however, benefits have not been conclusively demonstrated, and not all probiotics have the same effects [25].

Marine‐Based

Snail venoms have potentially valuable effects, including inhibition of pain without the potential for addiction, but they are peptides, and delivery to target sites is challenging [26]. The one marketed pain medicine derived from snail venom, ziconotide (Prialt), cannot cross the blood‐brain barrier and therefore can only be administered intrathecally. For this reason, although ziconotide has advantages over morphine, it’s only used when morphine is not a possibility [27].

Primary Psychological Input

Mindfulness. Mindfulness meditation has been found to significantly reduce pain in experimental and clinical settings and to improve a wide spectrum of clinically relevant cognitive and health outcomes, including for low‐back pain and fibromyalgia [7, 42, 43]. There is increasing evidence linking mindfulness techniques to improved immune function, but the findings require further replication [44], and there haven’t been enough large, high‐quality studies to determine long‐term effects in rheumatic disease [45, 46]. It is unclear if the analgesic mechanisms supporting mindfulness meditation are distinct from or parallel to those engaged by placebo and/or slow, rhythmic breathing; however, there is emerging evidence suggesting that mindfulness meditation engages multiple unique neural mechanisms not mediated by endogenous opioids to reduce pain [47].

Hypnosis. A growing body of evidence suggests that hypnosis may be useful to manage some painful conditions [48, 49]. Findings from a few studies have demonstrated that training patients in the use of self‐hypnosis significantly reduced their need for sedatives and analgesia when undergoing interventional radiological procedures [50].

Biofeedback. The efficacy of biofeedback has been evaluated in numerous studies for tension headaches, with positive results. Several studies have shown biofeedback decreased the frequency of both pediatric and adult migraines, with some showing an effect lasting over an average follow‐up phase of 17 months [51, 52].

Placebo. Contextual factors, including patient–clinician interactions and the expectation of benefit, can contribute to improvements in pain. Although this phenomenon is called the “placebo effect,” it can occur with any treatment, not just placebos, and may lead to enhanced outcomes [21, 53]. Understanding psychoneurobiological mechanisms underlying placebo analgesia may lead to shaping the clinician–patient relationship, reducing the use of analgesic drugs, and training the patient to become an active agent of the therapy [54].

Primary Physical Input

Acupuncture. For patients with low‐back pain, acupuncture has been associated with lower pain intensity compared to usual care or simulated acupuncture [33]. Acupuncture can be a helpful and reasonable referral option for other chronic pain conditions [33], including fibromyalgia [55], headaches [33. 56], and OA [32, 57, 58]. Auricular acupuncture, either as a stand‐alone therapy or as an adjunct technique, has shown potential benefits for acute pain relief [59].

Spinal manipulation. Spinal manipulation has been shown to produce modest, short‐term effects on chronic low‐back pain [6, 7]. Other studies have found that spinal manipulation is as effective as other interventions for reducing pain and improving function [60, 61].

Massage. There is low‐ to moderate‐quality evidence that massage therapy is superior to nonactive therapies in reducing arthritis pain and improving functional outcomes [62]. Massage may provide short‐term relief from low‐back pain, but the evidence is not of high quality [11]. There is some evidence that massage has a positive effect on migraine, tension headaches, and neck pain [56, 63].